Compositions containing a carbonamidoquinoxaline-di-n-oxide and method of using same

ABSTRACT

2-Formyloximido-3-aminocarbonylquinoxaline-1,4-di-N-oxides are antimicrobial agents. The compounds, of which 2formylcarbomethoxyhydrazine-3-dimethylaminocarbonylquinoxaline1,4-di-N -oxide is a typical embodiment, are prepared from the reaction of the corresponding 2-bis(halogeno)methylquinoxaline derivative and hydroxylamine or an appropriate hydrazinocarbonic acid ester in the presence of a primary or secondary amine and water.

United States Patent Seng et al. 1 July 22, 1975 15 1 COMPOSITIONS CONTAINING A 3.598.820 8/1971 Leay et al. 260/250 ON 3.660.401 5/1972 Derkel Hammer et al.. 260/250 ON CARBONAMlDOQUlNOXALINE-DI-N- OXIDE AND METHOD OF USING SAME Inventors: Florin Seng, Cologne; Kurt Ley, Odenthal-Globusch; Karl Georg Metzger, wuppertal Elberfeld, all of Germany Assignee: Bayer Aktiengesellschatt, Germany Filed: Sept. 20, 1973 Appl. No.: 399,445

Related US. Application Data Division of Ser. No. 249,121, May 1, 1972.

Foreign Application Priority Data May 7, 1971 Germany 2122572 US. Cl 424/248; 424/250 Int. Cl A61! 27/00 Field of Search 424/250, 248

References Cited UNITED STATES PATENTS 2/1968 Johnston 260/240 G OTHER PUBLICATIONS McBee et al., J. of Org. Chem., Vol. 30, pp.

Houben-Weyl, Methoden Der Organischen Chemie, Band x/l p. 1119, Georg Thieme Verlag, Stuttgart, Germany, 1971.

Primary Examiner-Jerome D. Goldberg [57] ABSTRACT 2-Formy1oximido-3-aminocarbonylquinoxaline1,4'di- N-oxides are antimicrobial agents. The compounds, of which Z-formylcarbomethoxyhydrazine-3dimethy1- aminocarbonylquinoxaline-1.4-di-N -oxide is a typical embodiment. are prepared from the reaction of the corresponding 2-bis(halogeno)methylquinoxaline derivative and hydroxylamine or an appropriate by drazinocarbonic acid ester in the presence of a pri mary or secondary amine and water.

83 Claims, No Drawings 1 COMPOSITIONS CONTAINING A CARBONAMIDOQUINOXALINE-DI-N-OXIDE AND METHOD OF USING SAME In the above, X is chloro or fluoro and R, R and Z are as defined above.

The reaction is carried out at temperatures from about to about 50C, preferably between 10 and This is a division of application Ser. NO- 249,1 1, 30C. at normal or elevated pressure, generally normal filed May 1, 1972. pressure.

The present invention relates to derivatives of 2- P f bl 1 t 2 mol of the hydrazine reactant or formyl-3-carbon mi oquinoxaline-di-N xi i0 hydroxylamine, and preferably 2 mols of the primary or methods for their production and use 35 antimicrobial secondary amine are used per mol at the high. agents and feed additives, and to compositions adapted l0 alogehomethyl compound, The amount of the amine these uses employed can however be varied within wide limits.

Particular, this invention Provides y The nature of the primary or secondary amine used is CarbonamidoqUihOXahhe'di'N'OXide compounds of the relatively unimportant and it is possible to use alkyl. formula: aralkyl, or aromatic amines such as methylamine, eth- 0 ylamine, propylamine, dimethylamine, methylethyla- 1 mine, ethylpropylamine, diethylamine and the like. The

i R b d d h l CO4 amines can e intro uce Into t e reaction so ution as 2 gases or be in the form of their aqueous solutions. The R reaction is preferably conducted in an inert organic solvent, particularly a polar organic solvent such as alka- N =2 nol, as for example methanol or ethanol; alkanoic nil triles such as acetonitrile, dimethylformamide and the 0 like. Mixtures of these and of water can also be emwherein ployed. It is advantageous to carry out the reaction in each of R and R independent of the other, is hydrothe Presehee of wateh Preferably of to p gcn, lower alkyi hydroxyuowcr aikyi), (iowcr aikoxy) cially l to 20% by weight of water relative to the weight lower alkyl cyclgpentyl cyclohexyl or cycloheptyl or of thfi Solvent. Even Catalytic amounts of water can fa- R and R together with the nitrogen atom to hi h vorably influence the reaction. Thus the bis(halogeno)- they are attached, are pyrrolidino, piperidino, hexamemethyl compound is Suspended in one of the solvents ihyleneimino morpholino or thiomorpholino; and hydroxylamine or the hydrazine derivative and water Z i =N. O}-[ or are added, and approximately the calculated amount of a primary of secondary amine is added dropwise, with Y cooling if necessary. The compounds thus produced I 3 are isolated by convention methods. The quinoxaline derivates of this invention show in which Y is an oxygen or lf atom d R i lower strong antimicrobial effects. This activity can be obaikyi, hydroxyuower aikyna lower aikoxyuowcr aikyi), served against Gram positive and Gram negative bactepyi-idyi, i which each f R and i d ria, such as: Enterobacteriaceae, for example Escheripendent of the other, is hydrogen, lower alkyl, hydrox 40 chiae, especially Escherichia coli; Proleae, for example (iowcr ik i or lower ik fl ik i) R d Proteus vulgaris, Proteus mirabilis, Proteus morgam'i R together i h h nitrogen atom to hi h th are and Proteus rettgeri; Klebsielleae, for example Klebsiella attached are lidi i idi h pneumoniae; Salmonelleae; Pseudomonadaceae, for exh i i i h li or hi h h ample Pseudomonas aeruginosa; Aeromonas, for exam- The term lower alkyl denotes a univalent saturated P Aemmonas liqllefafiens; Cilostridiat for example b h d or i ht h d b h i nt i i g stridium botulinum and Clostridium tetam'; Cocci, espefrom 1 to 6 carbon atoms. Representative of such lower cially Staphylococci, for example Staphylococcus analkyl groups are thus methyl, ethyl, propyl, isopropyl, reus; Streptococci, for example Streptococcus pyogenes; butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl, Enterococci, for example Streptococcus faecalis; Myconeopentyl, tert.pentyl, hexyl, and the like. plasmae, for example Mycoplasma pneumoniae and My- The term lower alkoxy denotes a straight or branched coplasma hominis; Mycobacreria; Pasteu rella, for examhydrocarbon chain bound to the remainder of the molple Pasteurella multocida; and Bordetella, for example ecule through an ethereal oxygen atom as, for example, Bordetella bronchiseptica. As a result of this activity and methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutheir low toxicity, the compounds are useful in human toxy, pentoxy and hexoxy. and veterinary medicine in the treatment of infections These compounds are obtained by allowing a 2-bis in animals caused by Gram positive and Gram negative (halogeno)methyl-3-carbonamidoquinoxaline to react bacteria and by mycoplasma. Infections of the respirawith hydroxylamine or hydrazine derivative in the prestory tracts in poultry, especially in chicks, and mastitis ence of a primary or secondary amine. This reaction of cows can be mentioned as particularly responsive to may be represented as follows: such treatment.

,2 con:

i( ciix The method of treatment of microbial infections in animals according to this invention comprises the administration to the animal of an antimicrobially effective amount of a quinoxaline of Formula I. The amount administered will of course depend upon the nature and severity of the infection, whether the treatment is curative or prophylactic. the age and condition of the recipient of the treatment and the method of administration and dosage regimen. Generally. however, a suitable response is observed with daily doses of from I to 100 mg/kg of body weight, especially I to 80 mg/kg. This of course must be adjusted to the individual case, utilizing sound professional judgment and careful observation of the response obtained.

As representative of the spectrum of antimicrobial activity for these compounds, the following representative minimum inhibitory concentrations shown on Tables A, B and C can be noted:

Table A Table C Compound of Alva/[genes Bordelellu Aeromonux Myro- Example faecalis brwu'lzi- Iiquefuciens bacterium No. ATCC .it'prir'u species I00 I00 I00 I00 I 1 I00 I00 I00 I00 I2 I00 100 I00 100 I3 I00 I00 I00 I00 I4 I00 I00 I00 I5 I00 I00 I00 I00 I6 I00 I00 I00 I7 I00 100 I00 I00 I8 I00 I00 I00 I00 I9 I00 I00 I00 40 I00 100 I00 I00 I00 2| I00 I00 1 I00 22 I00 I00 0.] I00 23 I00 I00 I00 I00 24 I00 100 I00 I00 25 I00 I00 I00 26 I00 I00 I00 27 I00 I00 100 28 I00 I00 I00 29 I00 I00 I00 Minimum Inhibitory Concentrations in Vitro, in ug/ml of Medium Compound of Klebsiella Staphylo- Strepto- Bcherichia Proteus Example coccus C(KCUJ coli vulgaris No. 63 8085 aureur I33 pyogenes C I65 A 261 species I0 100 I00 I00 I00 l I00 100 I00 100 12 I00 100 I0 100 I00 I3 100 10 100 I00 I00 I00 I00 I4 I00 100 I00 15 I00 100 I00 I0 100 100 l6 100 I00 100 I7 100 I0 100 100 I00 I00 I8 100 I0 100 I00 I00 I00 I00 [9 I00 I00 I00 I00 100 I00 100 26 I00 I0 I00 100 100 27 100 100 Table B The compounds of the present invention are administered parenterally or orally in any of the usual pharma- Com- Closlridium M 'roplasnm p ceutical forms. These include solid and liquid oral unit g elm dosage forms such as tablets, capsules, powders, sus- Example relani bomlinum MS S gran nmlm- Pensions, solutions syrups and the like! including Nov (Mn tained release preparations, and fluid injectable forms ATCC such as sterile solutions and suspensions. The term unit 10 m 10 100 m 10 dosage form as used in this specification and the claims :5 :8 :8 g :8 refer to physically discrete units to be administered in I 3 100 100 100 m0 m0 100 single or multiple dosage to animals, each unit contain- :88 :88 :88 I00 ing a predetermined quantity of active material in asso- 16 mo [00 m0 [00 mo ciation with the required diluent, carrier or vehicle. I7 I00 I00 100 100 100 100 The quantity of active material is that calculated to :3 produce the desired therapeutic effect upon adminis- 20 100 100 m m m0 m0 tration of one or more of such units. 5; 1 3 :8 Powders are prepared by comminuting the com- 23 I00 1 100 I00 l 00 pound to a suitable fine size and mixing with a similarly i; l I00 I00 100 comminuted diluent pharmaceutical carrier such as an 26 mo edible carbohydrate material as for example. starch. g; 188 100 100 m sweetening, flavoring, preservative, dispersing and col- 1 100 I00 100 29 100 00 I00 mo 00 I00 ortng agents can also be present.

Capsules are made by preparing a powder mixture as described above and filling formed gelatin sheaths. A lubricant such as talc, magnesium stearate and calcium stearate can be added to the powder mixture as an adjuvant before the filling operation; a glidant such as colhicle can be provided for mixing prior to administration.

In addition to their therapeutic use, the new compounds can also be used to promote the growth and imloidal Silica y be added to improve flow properties; 5 prove feed utilization in animals, especially in raising a disintegrating T Solubillling agent y be added to young animals and fat-stock animals, as for example, improve the availability of the medicament when the l i lets and chicks. capsule is gested. The compounds can be administered in the feedstuff. Tablets are made by preparing a powder miXtu in special feedstuff preparations, in preparations congramllatlflg slugging adding a lubricant and dislntetaining vitamins and/or mineral salts, or in the drinking grant and pressing into tablets. A powder mixture s water. Such administration of the compounds permits prepared by mixing the compound, suitably commiprevention or treatment of infections caused by Gram nuted, with a diluent or base such as starch, sucrose, negative and by Gram positive bacteria and by mycokaolin, (Calcium Phosphate and the like The Powder plasma, and additionally contributes to a more rapid mixture can be granulated y Wetting with a binder {5 growth of the animals and to better feed efiiciency. In Such as y p starch Paste, acacia mucilage or this embodiment, the compounds are preferably mixed tions of cellulQsle or Polymeric materials and forcing into the feedstuff or the drinking water in a concentrathrough a screen. As an alternative to granulating, the tion of 1 to 200 ppm. P mixture can be through the tablet machine The use of these compounds as feed additives can be and the resulting impel'feetly formed Slugs broke" into seen from the following feeding experiments (Table granules. The granules can be lubricated to prevent 1)) sticking to the tablet forming (CS means Of the addiin groups of wcre kept in cages and suption of stearic acid, a stearate salt, talc or mineral oil. li d ith ate ad libitum and a complete chick feed The lubricated mixture is then compressed into tablets. i whi h was intimately mixed the indicated amount The medicaments can also be combined with free flowof the test compound. The results are as follows:

Table D Chick Fattening Test Using the Compound of Example 20 Average Weight Absolute Weight Relative Weight lnltlal Weight of each animal Increase (g) of Increase ('56) Concentration (g) of each r each after after ppm animal 14 days 28 days 14 days 28 days 14 days 28 days Test 1 Control 0 59.3 170.8 335.2 111.5 275.9 100.0 100.0 Compound of Example 20 59.3 179.2 346.6 119.9 287.3 107.4 104.1

Test 2 Control 0 59.1 168.3 351.6 109.2 292.5 100.0 100.0 Compound of 10 59.1 173.3 358.3 114.2 299.2 104.5 102.2 Example 20 20 59.1 175.8 360.0 116.7 300.9 106.8 102.8

ing inert carriers and compressed into tablets directly without going through the granulating or slugging steps. A protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as syrups and elixirs can be prepared in unit dosage form so that a given quantity, eg. a teaspoonful, contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous sucrose solution while elixirs are prepared through the use of a nontoxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle in which it is insoluble.

Fluid unit dosage forms for parenteral administration can be prepared by suspending or dissolving a measured amount of the compound in a non-toxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium and sterilizing the suspension or solution. Alternatively a measured amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed. An accompanying vial or ve- The following examples will serve to further typify the nature of this invention without a limitation on the scope thereof:

EXAMPLE 1 2-formylcarbomethoxyhydrazone-3- methylaminocarbonylquinoxaline-l ,4-di-N-oxide 'r @ENI comma I L CH=N-N'1ICO0CH3 7 8 hol and l() ml of water. After 5 hours the product is fil- Cominued tered off and 25 g (78.5% of theory) of 2- l N R t A formylcarbomethoxyhydrazine-3- Exdmp e we methylaminocarbonylquinoxalinel ,4-di-N-oxide are obtained as yellow crystals which after recrystallization 5 l4 g. -aii dm ei i from acetic acid melt at 228C. with decomposition. H g g gfg:gg1g:g "g lfilgg& lfr;g:g

carboxylquinoxaline l ,4-dioxide l6 2-dichloromethyl-3-cyclohexylaminocarboxylq uinoxalinel .4-dioxide Analysis: C H,;,N O,-, (3]9] l7 2-dlChl0l'Omlhyl:Z-ISOPI'OPylfUflIflO- Calculated: C 49.0% H 4.0% N 219% I0 carboxylquinogalnge-lfiiidio tide Found: C 4&8? H 4.07 N 2l.97 l8 2dichlor0met y -et y aminocarboxylquinoxaline l A-dioxide l9 2-diehlorometl1yl3-methy aminocarboxylquinoxalinel A-dioxide The 2-dichlorometh l-3-carbox lic acidy fifiy y l y y y aminocarboxylquinoxaline-l 4-dioxide methylamidoquinoxaline-di-N-oxide required as the [5 2| MicmommfihylGmomholinw starting compound. of the formula carboxylquinoxaline-ll;4-dioxide 22 2-dichloromethyl-3-et ylaminocarbox lquinoxaline' l ,4-dioxide y i g 23 2dichloromethyl-3-n-propylaminocarboxylquinoxalinel ,4-dioxide N -NHCH3 24 2 dichloromethyl 3-i-propylarnin0- 20 carboxylquinoxalinel .4-di0xide I 2526 Z-dichloromethyl:3-methylan mo- N BC], carboxylquinoxalinel .4-dioxide l, 2 27-29 2-dgilororriethyl gfiihlglrgiyjhylcar xy quinoxa l i 0 3033 2'dichlorornethyl:3-l3-methoityethylcarboxylquinoxaline-l ,4-dloxide is obtained as follows: 340 g of chlorine are slowly 25 34 2 dichlomi iethyl 3-dieth ian inopassed into a solution of 466 g (2 mols) of 2-methyl-3- 35 gf fg w g ifikgfigxgfifi carboxylic acid-methylamidoquinoxaline-di-N-oxide carboxylquinoxaline-l.4-dioxide in acetic acid at 80-85C. Thereafter the mixture is 36 l t 'l 9 O carboxylquinoxaline-l,4-dioxide cooled to +l5 C and the precipitate which has formed 37 i h |,3 i is filtered off. 480 g (80%) of 2-dichloromethyl-3 30 cafboxylqumoxalme-l4-dlxlde carboxylic acid-methylamido-quinoxaline-di-N-oxide Example No; Ream, B are obtained as yellow crystals which after recrystallio 2 hydrazinocarbonic acid methyl ester zation from ethanol melt at l85 C. 3 hydrazinocarbonic acid B hydmxy ethyl ester 35 4 hydrazinocarbonic acid ethyl ester 5 hydrazinocarboxamide Anaiysfs' (302) 6 N-morpholinocarbonylhydrazine Calculated. C 43.7% H 2.98% CI 216% 7 i i lh d Found: c 43.2% H 3.1% Ci 23.1% 8

9 hydrazinothiocarboxamide l0l8 hydrazinocarbonic acid methyl ester The remaining dichloro compounds required as start- 40 19.20 hydroxylamine ing compounds are obtainable analogously. 21 hydralinocafbflflic acid methyl 22-24 hydroxylamine EXAMPLES 2 37 25 hyldrlazinocarbonic acid B-hydroxyet y ester In a similar fashion to that described in Example l, the following reactants are allowed to react: ethyl ester 29 N-morpholinocarbonylhydrazine E N Reactam A 30 hydrazinocarbonic acid methyl ester 3i :ygrazinocarbonic acid ethyl ester I V 32 y roxylamine 2 9 s ,figs $r ftfi g fi aiggggg 33 hydrazinocarbonic acid B-hydroxyi0 2'dichloromethyl-3-piperidino- 3447 g l f' carboxylquinoxaline-l,4-dioxide y roxy amine Z-dichlorornethyl-3diethylaminocarboxy lquinoiialinel ,4-dioxi'de l 2 Z-dichloromethyl-3pyrr0lidinocarboxylquinoxalinel .4-dioxide The following tained:

o T N CO-N r I \112 i cn=z 1 Example R Melting No. N Z point R2 i (0c) 2 NCH5 ii-iiti-co-oca 2o3-2o4 What is claimed is:

1. An antibacterial composition comprising an antibacterially effective amount of a compound of the formula:

wherein each of R and R independent of the other, is hydrogen, lower alkyl, hydroxy(lower alkyl), (lower alkoxy)lower alkyl, cyclopentyl, cyclohexyl or cycloheptyl, or R and R together with the nitrogen atom to which they are attached, are pyrrolidino. piperidino, hexamethyleneimino, morpholino or thiomorpholino; and

Y ll :N-NH-C-R in which Y is an oxygen or sulfur atom and R is lower alkyl, hydroxy(lower alkoxy), lower alkoxy, pyridyl, or -NR R in which each of R and R, independent of the other, is hydrogen, lower alkyl, hydroxy(lower alkyl) or lower alkoxy(lower alkyl), or R and R, together with the nitrogen atom to which they are attached, are pyrrolidino, piperidino, hexamethyleneimino, morpholino or thiomorpholino, in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.

2. A composition according to claim 1 wherein each of R and R", independent of the other, are hydrogen, methyl, ethyl, propyl, Z-hydroxyethyl, Z-methoxyethyl, cyclohexyl or R and R together with the nitrogen atom to which they are attached, are pyrrolidino, piperidino or morpholino; and R is amino, morpholino, pyridino, methoxy, ethoxy or 2-hydroxyethoxy.

3. A composition according to claim 1 wherein the compound is 2-formylcarbomethoxyhydrazine-3- dimethylaminocarbonylquinoxaline-1,4-di-N-oxide.

4. A composition according to claim 1 wherein the compound is 2-formylcarbomethoxyhydrazine-3- morpholinocarbonylquinoxalinel ,4-di-N-oxide.

5. A composition according to claim 1 wherein the compound is 2-formylcarbomethoxyhydrazine-3- diethylaminocarbonylquinoxalinel ,4-di-N-oxide.

6. A composition according to claim 1 wherein the compound is 2-formylcarbomethoxyhydrazine-3- pyrrolidinocarbonylquinoxaline-l ,4-di-N-oxide.

7. A composition according to claim 1 wherein the compound is 2-formyloximido-3-(2- hydroxyethyl)aminocarbonylquinoxaline-l ,4-di-N- oxide.

8. A composition according to claim 1 wherein the compound is Z-formylcarbomethoxyhydrazine-3- piperidinocarbonylquinoxaline-1,4-di-N-oxide,

9. A composition according to claim 1 wherein the compound is 2-formyloximido-3- ethylaminocarbonylquinoxalinel ,4-di-N-oxide.

10. A composition according to claim 1 wherein the compound is 2-formyloximido-3-n.- propylaminocarbonylquinoxalinel ,4-di-N-oxide.

11. A composition according to claim 1 wherein the compound is 2-formyloximido-3-i.- propylaminocarbonylquinoxalainel ,4'di-N-oxide.

12. A composition according to claim 1 wherein the compound is 2-formylcarbo-( 2- hydroxyethoxy)hydrazine-3- methylaminocarbonylquinoxalinel ,4-di-N-oxide.

13. A composition according to claim 1 wherein the compound is 2-formylcarboethoxyhydrazine-3- methylaminocarbonylquinoxaline-l ,4-di-N-oxide.

14. A composition according to claim 1 wherein the compound is 2-formylcarbomethoxyhydrazine-3- methylaminocarbonylquinoxaline-l ,4-di-N-oxide.

15. A composition according to claim 1 wherein R and R are each methyl and Z is N-N- H-CO-OCH -CH -OH.

16. A composition according to claim 1 wherein R and R are each methyl and Z is NN- HCO-O-C H 17. A composition according to claim 1 wherein R and R are each methyl and Z is NNHCONH 18. A composition according to claim 1 wherein R and R are each methyl and Z is 19. A composition according to claim 1 wherein R and R are each methyl and Z is 20. A composition according to claim 1 wherein R and R are each methyl and Z is NOH.

21. A composition according to claim I wherein R and R are each methyl and Z is NNH-CSNH 22. A composition according to claim 1 wherein one of R and R is hydrogen and the other is methyl and Z is N-NH-COOCH 23. A composition according to claim 1 wherein one of R and R is hydrogen and the other is hydroxyethyl and Z is NNHCOOCH 24. A composition according to claim 1 wherein one of R and R is hydrogen and the other is propyl and Z is NNH-CO-OCH 25. A composition according to claim 1 wherein one of R and R is hydrogen and the other is cyclohexyl and Z is N-NH-COOCH 26. A composition according to claim 1 wherein one of R and R is hydrogen and the other is isopropyl and Z is NNHCOOCH and Z is 30. A composition according to claim 1 wherein one of R and R is hydrogen and the other is hydroxyethy] and 31. A composition according to claim 1 wherein one f R1 d R2 is hydrogen and the orhcrjs nudroz'uemul mid Z is Hit-INC) 32. A composition according to claim 1 wherein one of R and R is hydrogen and the other is methoxyethyl 33. A composition according to claim 1 wherein one of R and R is hydrogen and the other is methoxyethyl and Z is 34. A composition according to claim 1 wherein one of R and R is hydrogen and the other is methoxyethyl and Z is NOH.

35. A composition according to claim 1 wherein one of R and R is hydrogen and the other is methoxyethyl and Z is 36. A composition according to claim 1 wherein R and R are each ethyl and Z is NOH.

37. A composition according to claim 1 wherein R and R together with the nitrogen atom to which they are attached are and z is NOH.

38. A composition according to claim 1 wherein R and R together with the nitrogen atom to which they are attached are and Z is NOH.

39. A composition according to claim I wherein R and R together with the nitrogen atom to which they are attached are and Z is NOH.

40. A composition according to claim 1 in parenteral administration form.

41. A composition according to claim 1 in oral administration form.

42. A method of treating bacterial infections in humans and animals which comprises administering to said infected animal or human an antibacterially effective amount of a compound of the formula:

wherein each of R and R independent of the other, is hydrogen, lower alkyl, hydroxy(lower alkyl), (lower alkoxy)lower alkyl, cyclopenty], cyclohexyl or cycloheptyl, or R and R together with the nitrogen atom to which they are attached, are pyrrolidino, piperidino, hexamethyleneimino, morpholino or thiomorpholino; and

i =N-NH-C-R3 in which Y is an oxygen or sulfur atom and R is lower alkyl, hydroxy(lower alkoxy), lower alkoxy, pyridyl, or NRR in which each of R and R independent of the other, is hydrogen, lower alkyl, hydroxy(lower alkyl) or lower alkoxy(lower alkyl), or R and R, together with the nitrogen atom to which they are attached, are pyrrolidino, piperidino, hexamethyleneimino, morpholino or thiomorpholino, in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.

43. A method according to claim 42 wherein each of R and R independent of the other, are hydrogen, methyl, ethyl, propyl, Lhydroxyethyl, 2-methoxyethyl, cyclohexyl or R and R together with the nitrogen atom to which they are attached, are pyrrolidino, piper- 17 idino or morpholino; and R is amino, morpholino, pyridino, methoxy, ethoxy or 2-hydroxyethoxy.

44. A method according to claim 42 wherein the compound is 2-formylcarbomethoxyhydrazine-3- dimethylaminocarbonylquinoxaline-l ,4-di-N-oxide.

45. A method according to claim 42 wherein the compound is 2-formylcarbomethoxyhydrazine-3 morpho]inocarbonylquinoxaline-l ,4-di-N-oxide.

46. A method according to claim 42 wherein the compound is 2-formylcarbomethoxyhydrazine-3- diethylaminocarbonylquinoxaline-1,4-di-N-oxide.

47. A method according to claim 42 wherein the compound is. 2-formylcarbomethoxyhydrazine-3- pyrrolidinocarbonylquinoxalinel ,4-di-N-oxide.

48. A method according to claim 42 wherein the compound is 2-formyloximido-3-(2- hydroxyethyl)aminocarbonylquinoxaline-l ,4-di-N- oxide.

49. A method according to claim 42 wherein the compound is 2-formylcarbomethoxyhydrazine-3- piperidinocarbonylquinoxaline1,4-di-N-oxide.

50. A method according to claim 42 wherein the compound is 2-formyloximido-3- ethylaminocarbonylquinoxalinel ,4-di-N-oxide.

51. A method according to claim 42 wherein the compound is 2-formyloximido-3-n.- propylaminocarbonylquinoxalinel ,4-di-N-oxide.

52. A method according to claim 42 wherein the compound is 2-formyloximido-3-i.- propylaminocarbonylquinoxaline-1,4-di-N-oxide.

53. A method according to claim 42 wherein the compound is 2-formylcarbo-( 2- hydroxyethoxy)hydrazine-3- methylaminocarbonylquinoxaline-l ,4-di-N-oxide.

54. A method according to claim 42 wherein the compound is 2-formylcarbethoxyhydrazine-3- methylaminocarbonylquinoxaline-l ,4-di-N-oxide.

55. A method according to claim 42 wherein the compound is 2-formylcarbomethoxyhydrazine-3- methylaminocarbonylquinoxaline-l ,4-di-N-oxide.

56. A method according to claim 42 wherein R and R are each methyl and Z is NNH-COOCH- CH -OH.

57. A method according to claim 42 wherein R and R" are each methyl and Z is NNHCOOC H 58. A method according to claim 42 wherein R and R are each methyl and Z is NNH-CO-NH 59. A method according to claim 42 wherein R and R are each methyl and Z is 60. A method according to claim 42 wherein R and R are each methyl and Z is 61. A method according to claim 42 wherein R and R are each methyl and Z is NOH.

62. A method according to claim 42 wherein R and R are each methyl and Z is N-NH-CSNH 63. A method according to claim 42 wherein one of R and R is hydrogen and the other is methyl and Z is N-NHCOOCH 64. A method according to claim 42 wherein one of R and R is hydrogen and the other is hydroxyethyl and Z is N-NHCOOCH 65. A method according to claim 42 wherein one of R and R is hydrogen and the other is propyl and Z is N-NHCO-OCH 66. A method according to claim 42 wherein one of R and R is hydrogen and the other is cyclohexyl and Z is NNHCOOCH 67. A method according to claim 42 wherein one of R and R is hydrogen and the other is isopropyl and Z is NNHCOOCH 68. A method according to claim 42 wherein one of R and R is hydrogen and the other is ethyl and Z is N-NHCOOCH 69. A method according to claim 42 wherein one of R and R is hydrogen and the other is methyl and Z is NOH.

70. A method according to claim 42 wherein one of R and R is hydrogen and the other is hydroxyethyl and Z is N-NR-fi CC 11 0 71. A method according to claim 42 wherein one of R and R is hydrogen and the other is hydroxyethyl and Z is 72. A method according to claim 42 wherein one of R and R is hydrogen and the other is hydroxyethyl and Z is 73. A method according to claim 42 wherein one of R and R is hydrogen and the other is methoxyethyl and Z is 74. A method according to claim 42 wherein one of R and R is hydrogen and the other is methoxyethyl and Z is 75. A method according to claim 42 wherein one of R and R is hydrogen and the other is methoxyethyl and Z is NOH.

76. A method according to claim 42 wherein one of R and R is hydrogen and the other is methoxyethyl and Z is 77. A method according to claim 42 wherein R and R are each ethyl and Z is NOH.

78. A method according to claim 42 wherein R and R together with the nitrogen atom to which they are attached are and Z is NOH.

79. A method according to claim 42 wherein R and R together with the nitrogen atom to which they are attached are and Z is NOH.

is present in the amount of l to I00 mg/kg of body weight. 

1. AN ANTIBACTERIAL COMPOSITION COMPRISING AN ANTIBACTERIALLY EFFECTIVE AOUNT OF A COMPOUND OF THE FORMULA:
 2. A composition according to claim 1 wherein each of R1 and R2, independent of the other, are hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl, 2-methoxyethyl, cyclohexyl or R1 and R2, together with the nitrogen atom to which they are attached, are pyrrolidino, piperidino or morpholino; and R3 is amino, morpholino, pyridino, methoxy, ethoxy or 2-hydroxyethoxy.
 3. A composition according to claim 1 wherein the compound is 2-formylcarbomethoxyhydrazine-3-dimethylaminocarbonylquinoxaline-1, 4-di-N-oxide.
 4. A composition according to claim 1 wherein the compound is 2-formylcarbomethoxyhydrazine-3-morpholinocarbonylquinoxaline-1,4-di-N -oxide.
 5. A composition according to claim 1 wherein the compound is 2-formylcarbomethoxyhydrazine-3-diethylaminocarbonylquinoxaline-1, 4-di-N-oxide.
 6. A composition according to claim 1 wherein the compound is 2-formylcarbomethoxyhydrazine-3-pyrrolidinocarbonylquinoxalIne-1,4-di-N -oxide.
 7. A composition according to claim 1 wherein the compound is 2-formyloximido-3-(2-hydroxyethyl)aminocarbonylquinoxaline-1,4-di-N-oxide.
 8. A composition according to claim 1 wherein the compound is 2-formylcarbomethoxyhydrazine-3-piperidinocarbonylquinoxaline-1,4-di-N -oxide.
 9. A composition according to claim 1 wherein the compound is 2-formyloximido-3-ethylaminocarbonylquinoxaline-1,4-di-N-oxide.
 10. A composition according to claim 1 wherein the compound is 2-formyloximido-3-n.-propylaminocarbonylquinoxaline-1,4-di-N-oxide.
 11. A composition according to claim 1 wherein the compound is 2-formyloximido-3-i.-propylaminocarbonylquinoxalaine-1,4-di-N-oxide.
 12. A composition according to claim 1 wherein the compound is 2-formylcarbo-(2-hydroxyethoxy)hydrazine-3-methylaminocarbonylquinoxaline -1,4-di-N-oxide.
 13. A composition according to claim 1 wherein the compound is 2-formylcarboethoxyhydrazine-3-methylaminocarbonylquinoxaline-1, 4-di-N-oxide.
 14. A composition according to claim 1 wherein the compound is 2-formylcarbomethoxyhydrazine-3-methylaminocarbonylquinoxaline-1, 4-di-N-oxide.
 15. A composition according to claim 1 wherein R1 and R2 are each methyl and Z is N-NH-CO-O-CH2-CH2-OH.
 16. A composition according to claim 1 wherein R1 and R2 are each methyl and Z is N-NH-CO-O-C2H5.
 17. A composition according to claim 1 wherein R1 and R2 are each methyl and Z is N-NH-CO-NH2.
 18. A composition according to claim 1 wherein R1 and R2 are each methyl and Z is
 19. A composition according to claim 1 wherein R1 and R2 are each methyl and Z is
 20. A composition according to claim 1 wherein R1 and R2 are each methyl and Z is NOH.
 21. A composition according to claim 1 wherein R1 and R2 are each methyl and Z is N-NH-CS-NH2.
 22. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is methyl and Z is N-NH-CO-OCH3.
 23. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is hydroxyethyl and Z is N-NH-CO-OCH3.
 24. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is propyl and Z is N-NH-CO-OCH3.
 25. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is cyclohexyl and Z is N-NH-CO-OCH3.
 26. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is isopropyl and Z is N-NH-CO-OCH3.
 27. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is ethyl and Z is N-NH-CO-OCH3.
 28. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is methyl and Z is NOH.
 29. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is hydroxyethyl and Z is
 30. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is hydroxyethyl and
 31. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is hydroxyethyl and Z is
 32. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is methoxyethyl and Z is
 33. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the Other is methoxyethyl and Z is
 34. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is methoxyethyl and Z is NOH.
 35. A composition according to claim 1 wherein one of R1 and R2 is hydrogen and the other is methoxyethyl and z is
 36. A composition according to claim 1 wherein R1 and R2 are each ethyl and Z is NOH.
 37. A composition according to claim 1 wherein R1 and R2 together with the nitrogen atom to which they are attached are
 38. A composition according to claim 1 wherein R1 and R2 together with the nitrogen atom to which they are attached are
 39. A composition according to claim 1 wherein R1 and R2 together with the nitrogen atom to which they are attached are
 40. A composition according to claim 1 in parenteral administration form.
 41. A composition according to claim 1 in oral administration form.
 42. A method of treating bacterial infections in humans and animals which comprises administering to said infected animal or human an antibacterially effective amount of a compound of the formula:
 43. A method according to claim 42 wherein each of R1 and R2, independent of the other, are hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl, 2-methoxyethyl, cyclohexyl or R1 and R2, together with the nitrogen atom to which they are attached, are pyrrolidino, piperidino or morpholino; and R3 is amino, morpholino, pyridino, methoxy, ethoxy or 2-hydroxyethoxy.
 44. A method according to claim 42 wherein the compound is 2-formylcarbomethoxyhydrazine-3-dimethylaminocarbonylquinoxaline-1, 4-di-N-oxide.
 45. A method according to claim 42 wherein the compound is 2-formylcarbomethoxyhydrazine-3-morpholinocarbonylquinoxaline-1,4-di-N -oxide.
 46. A method according to claim 42 wherein the compound is 2-formylcarbomethoxyhydrazine-3-diethylaminocarbonylquinoxaline-1, 4-di-N-oxide.
 47. A method according to claim 42 wherein the compound is 2-formylcarbomethoxyhydrazine-3-pyrrolidinocarbonylquinoxaline-1,4-di-N -oxide.
 48. A method according to claim 42 wherein the compound is 2-formyloximido-3-(2-hydroxyethyl)aminocarbonylquinoxaline-1,4-di-N-oxide.
 49. A method according to claim 42 wherein the compound is 2-formylcarbomethoxyhydrazine-3-piperidinocarbonylquinoxaline-1,4-di-N -oxide.
 50. A method according to claim 42 wherein the compound is 2-formyloximido-3-ethylaminocarbonylquinoxaline-1,4-di-N-oxide.
 51. A method according to claim 42 wherein the compound is 2-formyloximido-3-n.-propylaminocarbonylquinoxaline-1,4-di-N-oxide.
 52. A method according to claim 42 wherein the compouNd is 2-formyloximido-3-i.-propylaminocarbonylquinoxaline-1,4-di-N-oxide.
 53. A method according to claim 42 wherein the compound is 2-formylcarbo-(2-hydroxyethoxy)hydrazine-3-methylaminocarbonylquinoxaline -1,4-di-N-oxide.
 54. A method according to claim 42 wherein the compound is 2-formylcarbethoxyhydrazine-3-methylaminocarbonylquinoxaline-1,4-di-N-oxide.
 55. A method according to claim 42 wherein the compound is 2-formylcarbomethoxyhydrazine-3-methylaminocarbonylquinoxaline-1,4-di-N -oxide.
 56. A method according to claim 42 wherein R1 and R2 are each methyl and Z is N-NH-CO-O-CH2-CH2-OH.
 57. A method according to claim 42 wherein R1 and R2 are each methyl and Z is N-NH-CO-O-C2H5.
 58. A method according to claim 42 wherein R1 and R2 are each methyl and Z is N-NH-CO-NH2.
 59. A method according to claim 42 wherein R1 and R2 are each methyl and Z is
 60. A method according to claim 42 wherein R1 and R2 are each methyl and Z is
 61. A method according to claim 42 wherein R1 and R2 are each methyl and Z is NOH.
 62. A method according to claim 42 wherein R1 and R2 are each methyl and Z is N-NH-CS-NH2.
 63. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is methyl and Z is N-NH-CO-OCH3.
 64. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is hydroxyethyl and Z is N-NH-CO-OCH3.
 65. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is propyl and Z is N-NH-CO-OCH3.
 66. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is cyclohexyl and Z is N-NH-CO-OCH3.
 67. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is isopropyl and Z is N-NH-CO-OCH3.
 68. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is ethyl and Z is N-NH-CO-OCH3.
 69. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is methyl and Z is NOH.
 70. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is hydroxyethyl and Z is
 71. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is hydroxyethyl and Z is
 72. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is hydroxyethyl and Z is
 73. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is methoxyethyl and Z is
 74. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is methoxyethyl and Z is
 75. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is methoxyethyl and Z is NOH.
 76. A method according to claim 42 wherein one of R1 and R2 is hydrogen and the other is methoxyethyl and Z is
 77. A method according to claim 42 wherein R1 and R2 are each ethyl and Z is NOH.
 78. A method according to claim 42 wherein R1 and R2 together with the nitrogen atom to which they are attached are v,155/5 and Z is NOH.
 79. A method according to claim 42 wherein R1 and R2 together with the nitrogen atom to which they are attached are
 80. A method according to claim 42 wherein R1 and R2 together with the nitrogen atom to which they are attached are
 81. A method according to claim 42 wherein the administration is parenteral.
 82. A method according to claim 42 wherein the administration is oral.
 83. The method of claim 42 wherein the compound is present in the amount of 1 to 100 mg/kg of body weight. 